Heart failure is a progressive and irreversible condition where loss of myocardial function results in severe disability and death. In many cases, a cause for the disease cannot be identified and those cases of unknown origin are grouped under the descriptive definition of "idiopathic" dilated cardiomyopathy (iDCM). Progressive misfolding of proteins is a common cause of many apparently unrelated chronic diseases such as primary systemic amyloidosis, diabetes, neurodegenerative diseases and inclusion body myositis and we propose that protein misfolding can be at the basis of at least some cases of iDCM. This hypothesis is based upon the observation of the presence, in the heart of patients affected by iDCM at early and late stage heart failure, of fibrillar aggregates as well as fibrillar fragments (oligomers) similar to what described in other diseases of protein. However, the causal relationship between protein aggregate and disease development remains inconclusive also for the known diseases of protein misfolding such as Alzheimer disease. In Alzheimer disease, the oligomeric fragments rather that the fibrillar aggregates have been suggested to exert a pathogenic effect leading to neuronal dysfunction and death mediated by increased intracellular Ca2+ and ER Ca2+ release. Defect in SR Ca2+ uptake and release are well known changes in the failing myocardium in human and animal models of heart failure. Similarly to the effect on neurons we showed that oligomers can alter intracellular Ca2+ content. Therefore, in this proposal we will test the hypothesis that iDCM can originate from a defect of protein folding leading to the accumulation of pathogenic oligomeric fragments affecting Ca2+ homeostasis. To test this hypothesis we will dissect the mechanism for the pathogenic effect of protein oligomers in vitro on human and mice cardiomyocytes acutely and chronically as well as in vivo using mice models of AD and models of iDCM caused by mutations in the gene causing AD. The finding of the current proposal may contribute to change our current understanding of cardiomyopathies as an organ specific defect of a more general biological process and most importantly a defect susceptible to drug targeting. PUBLIC HEALTH RELEVANCE: Congestive Heart Failure (HF) has reached epidemic proportions in the United States. The majority of cases of HF are ischemic in origin. In a smaller number of cases of non- ischemic origin, dilated cardiomyopathy (DCM) results from myocardial damage by toxic, infectious, or metabolic agents. Other causes include infiltrative disorders (amyloidosis, sarcoidosis) or they are genetically determined. When one of these causative events cannot be recognized, the myocardial disease is classified as idiopathic (iDCM). Heart transplant is currently the only therapeutic option in these cases, but is limited by the availability of organ donations and by the age threshold for the surgical intervention. Therefore an important issue is to understand the molecular mechanisms at the origin of the disease to expand better therapeutic options to a larger population. Recent studies highlight the recognition of the public health importance of a large number of diseases associated with defective folding of proteins leading to the accumulation of cytotoxic protein aggregates and clustered as conformational diseases. These include various neurodegenerative disorders such as Alzheimer Disease. Preliminary evidence suggests that iDCM may be included among these misfolding diseases. Also, mutations in the same genes causing Alzheimer diseases in a significant percentage of cases can be also at the origin of iDCM. Interestingly, the mechanism mediating the effect of these genetic variations may be linked to changes in the control of calcium (Ca2+) handling proteins and function causing defect in the contractile function as well as cell damages associated with the protein aggregation process, the component we are exploring in the current proposal. The incidence, prognosis and therapeutic option for iDCM therefore may be greatly advanced by establishing a fundamental understanding of key factors leading to the disease.